Some cancers are fueled by more than genetic mutations. About
two out of three breast cancers, for example, are aided by
estrogen, so blocking the hormone helps stop those tumors.
Inhibiting these
cancer enablers is a growing discipline in oncology research.

One such class of therapies is called
protease inhibitors—drugs
that block a protease necessary for a cancer cell to invade
and metastasize. Proteases are enzymes that cleave, or split,
proteins,
and researchers know they play a role in the growth and spread
of cancer.

“There is a widely accepted dogma that proteases are
bad,” says
Jaime R. Merchan, M.D., M.M.Sc., assistant professor and a
hematologist-oncologist at the University of Miami Sylvester
Comprehensive Cancer Center. “Block
the enzyme and the cell can’t spread.”

Merchan and colleagues have recently published
a study that challenges this dogma. He conducted experiments
where breast
cancer cells
were genetically “forced” to produce an excess of
two proteases—tissue plasminogen activator, or tPA, and
urokinase, or uPA. When they injected the cancer cells into
mice, the modified tumors were less likely to grow or metastasize
compared
with mice having unmodified control tumors. They also found
that in the protease-overexpressing tumors, overall survival
was one-third
longer in the tPA group and twice as long in the uPA group
compared with controls.

The researchers then tested whether the
anti-tumor effects were due to the enzymatic activity of
the proteases. They genetically
modified urokinase to make it “proteolytically inactive,” switching
off its ability to decompose proteins. Tumors expressing the
proteolytically inactive urokinase grew faster than tumors exposed
to “active” urokinase and at about the same rate
as untreated control tumors.

Curiously, the proteases stopped tumors
only in animal models (in vivo), not in isolated cancer cells
in the lab (in vitro). “That
led us to conclude that the proteases overexpressed by the tumors
are not directly toxic to the tumor cells, but that they block
tumor growth indirectly.” Merchan published an earlier
study showing that proteases of the plasminogen activator system
can cleave blood proteins and generate peptides that inhibit
angiogenesis, starving the tumors of blood.